In a review study published in the journal Trends in Pharmacological Sciences, the UAB research team defines the criteria that CAR immunotherapies for neurodegenerative diseases must meet to advance both conceptually and in trials that are still very preliminary.
The application of CAR immunotherapy to neurodegenerative diseases is limited by major challenges due to the complex nature of these pathologies and the heterogeneity of the deleterious molecules targeted for treatment. Nevertheless, despite the uncertainties, the early findings are encouraging to continue moving forward with research that is still in its very early stages. This is what a team of researchers from the Autonomous University of Barcelona (UAB) concluded in a review study published in an academic journal. Trends in pharmacology (cell group).
CAR immunotherapy allows immune cells to be engineered in the laboratory with high specificity to fight pathogenic molecules. This specificity is achieved by using genetic engineering to modify a patient’s immune cells to express synthetic proteins called chimeric antigen receptors (CARs) on their cell membranes. This receptor recognizes a target molecule and activates an immune response by cells expressing it. The engineered cells also incorporate various intracellular signaling modules for activation and safety.
In a published paper, UAB researchers cited previous clinical trials conducted using the CAR platform for neurodegenerative treatments, analyzing how different types of immune cells (effectors) can be used to modulate critical processes, from clearing toxic aggregates typical of diseases such as Alzheimer’s and Parkinson’s to rebalancing immunity.
This review allowed us to define what we believe are the fundamental principles that these treatments should meet in order to advance research. In addition to having high selection accuracy, they should be programmable, maintained over long periods of time, and controllable across different contexts of disease evolution. And they can be based on effector cells such as macrophages, microglia, and regulatory T cells (Tregs). These cells are thought to be better suited to the multifactorial and chronic nature of neurodegenerative diseases than T lymphocytes, another type of effector that has been used with CAR-T therapy in oncology to treat some types of cancer, primarily of the blood system, and some autoimmune diseases.
In neurodegenerative diseases, instead of targeting simple, stable antigens, there are heterogeneous and evolving sets of aggregates and unfolded proteins with different conformations, aggregation states, and toxicity that are found in different brain regions and disease stages. These layers of complexity change the therapeutic goals of the CAR platforms we are investigating, from eradication to controlled modulation. ”
Salvador Ventura, Professor, Department of Biochemistry and Molecular Biology, Research Scientist, UAB Institute of Biotechnology and Biomedical Research
Main factors driving research
Controlling the activation and inactivation of CAR platforms has emerged as a key element to achieve precision immunomodulation. “As neurodegenerative diseases are progressive, we need a CAR system that functions stably and sustainably without causing toxic accumulation in the brain, an organ with low resistance to inflammation and irreversible neuronal damage,” emphasizes Julia Pesce, a researcher at IBB-UAB and first author of the paper.
In this sense, control systems with logic gates are increasingly being designed, inspired by Boolean principles (AND, OR, NOT, etc.), but they are still at the stage of conceptualization for neurodegeneration. Platforms with on-off control and conditional secretion of therapeutic molecules appear to be the most appropriate architecture for now to address aggregates while limiting neuroinflammation and collateral tissue damage.
Another important challenge for advancing research is to achieve higher molecular precision, make the binding of the receptor to the aggregates more robust, and better differentiate between functional and toxic aggregates.
The authors also propose different approaches to use effector cells depending on the disease stage and purpose. In the early stages of neurodegeneration, microglia and macrophages remove toxic aggregates and limit their accumulation and spread, and in the later stages, Tregs and microglia promote immune balance and counter inflammation. At more advanced stages, where aggregate removal strategies are inadequate, platforms including macrophages and microglia could be equipped with switchable systems to secrete immunomodulatory molecules or target other proteins to counteract the effects of aggregates.
Overall, despite the preliminary nature of clinical data from in vitro and mouse cell models, “the findings obtained so far make CAR platform-based immunomodulation increasingly plausible for the treatment of neurodegeneration,” said Salvador Ventura. “As in the case of recent astrocyte-based CAR therapies, we are seeing that immune cell engineering can open the door to intervene in processes in the central nervous system that were previously thought to be difficult or inaccessible for therapeutic intervention. Receptor structure If we manage to advance the safety control of and CAR therapies, we have the potential to expand the therapeutic repertoire for neurodegenerative diseases beyond the limits of conventional pharmacology and apply more effective and durable cellular intervention strategies in the medical field,” he concluded.
sauce:
Autonomous University of Barcelona (UAB)
Reference magazines:
Fish, G. others. (2026). Programmable CAR immunotherapy for neurodegenerative proteinopathies. Trends in pharmacology. DOI: 10.1016/j.tips.2026.02.009. https://www.sciencedirect.com/science/article/abs/pii/S0165614726000428?dgcid=author
